Inactivation of the VHL tumor suppressor gene is a common event in hereditary (VHL Disease) and non- hereditary clear cell renal carcinoma, which is the most common form of kidney cancer. The VHL gene product, pVHL, has many functions including acting as the substrate recognition component of an ubiquitin ligase complex that targets the alpha subunit of the heterodimeric transcription factor HIF for destruction. Genotype-phenotype correlations and preclinical models suggest that downregulation of HIF2a is both necessary and sufficient for pVHL to suppress renal carcinoma growth, thus validating HIF2a as a potential therapeutic target in this disease. Unfortunately, transcription factors such as HIF2a are historically difficult to inhibit with drug-like small organic molecules. As an alternative, we propose to inhibit HIF2a using siRNA. Recent studies suggest that siRNA can be effectively delivered in vivo when incorporated within nanoparticles targeted to the transferrin receptor. In specific aims 1 and 2 we will test whether this technology can be used to downregulate HIF2a in VHL-/- renal carcinoma lines grown orthotopically in nude mice and we will attempt to develop pharmacodynamic markers suitable for preclinical and clinical studies. In Aim 3 we will measure HIF2a and transferrin receptor levels in human kidney cancer samples to assess their relationship to each other and VHL loss, the influence of acquired resistance to VEGFR blockade on their expression, as well as their prognostic significance and ability to predict benefit to standard therapies. Finally, in Aim 4 we proposed an investigator initiated follow-on Phase lb trial to a Phase I industry sponsored first in man Phase I trial of HIF2a siRNA-containing nanoparticles. This Phase lb trial will be performed in a population of patients with advanced clear cell RCC selected based on tumor HIF2a expression and other factors identified in Aims 2 and 3 and will include correlative pharmacodynamic endpoints modeled after those developed in Aim 2. Taken together, this work, which clearly goes from bench-to-bedside, should establish the safety and therapeutic potential for targeting this critical etiologic factor in VHL -/- clear cell RCC using transferrin-targeted, siRNA-containing nanoparticle technology and lay the groundwork for future clinical development of this potentially exciting approach in patients with this disease. If successful, this trial would also have implications for other forms of cancer that are driven by undruggable oncoproteins.